1. Field of the Invention
The present invention is related to pharmaceutical compositions which increase the bioavailability of the proteinase inhibitors.
2. Description
It is well known in the art that a wide range of diseases are caused by retroviruses.
As far as is known at the present, AIDS is a disease of the immune system caused by the retrovirus HIV (Human Immunodeficiency Virus). According to estimates by the World Health Organization, the disease, which affects about 10 million people, is continuing to spread and in virtually all cases results in the death of the patient.
Retroviruses HIV-1 and HIV-2 have been identified as a cause of the disease and they have been characterized by molecular biology.
Retroviral protease is a proteolytic enzyme that, owing to an aspartate residue in the active center, is regarded as an aspartate protease and participates in the maturation of new infectious virions in infected cells in the reproductive cycle of a number of retroviruses.
For example, HIV-1 and HIV-2 each have in their genome a region that codes for a "gag-protease". That "gag-protease" is responsible for the correct proteolytic cleavage of the precursor proteins that are produced from the genome regions coding for the "Group Specific Antigens" (gag). During the cleavage, the structural proteins of the virus core are liberated. The "gag-protease" itself is a component of a precursor protein encoded by the pol-genome region of HIV-1 and HIV-2, which protein also contains the regions for the "reverse transcriptase" and the "integrase" and is thought to be cleaved by autoproteolysis.
The "gag-protease" cleaves the major core protein p24 of HIV-1 and HIV-2 preferentially N-terminally of proline residues, for example in the divalent residues Phe-Pro, Leu-Pro, or Tyr-Pro. It is a protease having a catalytically active aspartate residue in the active center, a so-called aspartate protease.
As used herein, proteinase inhibitor refers to those compounds which inhibit aspartate proteases of viral origin and which are useful in the prophylaxis or treatment of viral infections caused by retroviruses, such as HIV, in mammals, both human and non-human. Details of the design of such proteinase inhibitors can be found, for example, in Roberts, N. A., et al., Science, 248, 358 (Apr. 20, 1990); Overton, H. A., et al., Virology, 179, 508 (1990); Tucker, T. J., et al., J. Med. Chem., 35, 2525 (1992); and Phylip, L. H., et al., FEBS Letters, 314, 449 (1992).
Because of the hydrophobic and/or lipophilic character of proteinase inhibitors, pharmaceutical formulations thereof with conventional solid or liquid pharmaceutical excipients tend to have disadvantages. For example the proteinase inhibitor may not be satisfactorily absorbed. Among the inherent factors known to affect absorption are the method of manufacture or method of compounding; the particle size and crystal form or polymorph of the drug substance; and the diluents and excipients used in formulating the dosage form, including carriers, fillers, binders, disintegrating agents, lubricants, coatings, solvents, suspending agents, and dyes.
A requirement for therapeutic effectiveness in vivo is the achievement of good bioavailability, for example good absorptive capacity and/or a high blood level, also in the case of enteral, such as oral, administration, in order to obtain sufficiently high concentrations in the infected cells and/or good distribution within a host in need of treatment.
An additional requirement is that the unit dosage form have good stability or shelf life so that it can be stored conveniently (e.g., no refrigeration, i.e., at room temperature (about 20.degree. C.) for a long period of time (e.g., about two years).
While there are many known proposals to alleviate or overcome problems of this type, it has been found that many of these proposals are inadequate in the area of the proteinase inhibitors. It has, however, surprisingly been found that certain classes of glycerides used as carrier components of formulation do assist in alleviating these inadequacies. In particular, they enable achievement of better absorption and thus enhanced bioavailability and have good stability or shelf life over a long period of time.